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Full-Text Articles in Laboratory and Basic Science Research
A Catalog Of Scn1a Variants, Christoph Lossin
A Catalog Of Scn1a Variants, Christoph Lossin
Christoph Lossin, Ph.D.
Over the past 10 years mutations in voltage-gated sodium channels (Navs) have become closely associated with inheritable forms of epilepsy. One isoform in particular, Nav1.1 (gene symbol SCN1A), appears to be a superculprit, registering with more than 330 mutations to date. The associated phenotypes range from benign febrile seizures to extremely serious conditions, such as Dravet’s syndrome (SMEI). Despite the wealth of information, mutational analyses are cumbersome, owing to inconsistencies among the Nav1.1 sequences to which different research groups refer. Splicing variability is the core problem: Nav1.1 co-exists in three isoforms, two of them lack 11 or 28 amino acids …
Inhibition Of Astroglial Kir4.1 Channels By Selective Serotonin Reuptake Inhibitors, Y. Ohno, H. Hibino, Christoph Lossin, A. Inanobe, Y. Kurachi
Inhibition Of Astroglial Kir4.1 Channels By Selective Serotonin Reuptake Inhibitors, Y. Ohno, H. Hibino, Christoph Lossin, A. Inanobe, Y. Kurachi
Christoph Lossin, Ph.D.
The inwardly rectifying K+ (Kir) channel Kir4.1 is responsible for astroglial K+ buffering. We recently found that tricyclic antidepressants (TCAs) inhibit Kir4.1 channel currents, which suggests that astroglial Kir currents might be involved in the pharmacological action of antidepressants. We therefore further examined the effects of the currently most popular antidepressants, selective serotonin reuptake inhibitors (SSRIs), and other related agents on Kir4.1 channels heterologously expressed in HEK293T cells. The whole-cell patch clamp technique was used. Fluoxetine, the typical SSRI, inhibited Kir4.1 channel currents in a concentration-dependent manner with an IC50 value of 15.2 microM. The inhibitory effect of fluoxetine was …
Inhibition Of Astroglial Inwardly Rectifying Kir4.1 Channels By A Tricyclic Antidepressant, Nortriptyline., S. Su, Y. Ohno, Christoph Lossin, A. Inanobe, Y. Kurachi
Inhibition Of Astroglial Inwardly Rectifying Kir4.1 Channels By A Tricyclic Antidepressant, Nortriptyline., S. Su, Y. Ohno, Christoph Lossin, A. Inanobe, Y. Kurachi
Christoph Lossin, Ph.D.
The inwardly rectifying K(+) (Kir) channel Kir4.1 is responsible for astroglial K(+) buffering. We examined the effects of nortriptyline, a tricyclic antidepressant (TCA), on Kir4.1 channel currents heterologously expressed in HEK293T cells, using a whole-cell patch-clamp technique. Nortriptyline (3-300 microM) reversibly inhibited Kir4.1 currents in a concentration-dependent manner, whereas it marginally affected neuronal Kir2.1 currents. The inhibition of Kir4.1 channels by nortriptyline depended on the voltage difference from the K(+) equilibrium potential (E(K)), with greater potency at more positive potentials. Blocking kinetics of the drug could be described by first-order kinetics, where dissociation of the drug slowed down and association …
Single-Channel Properties Of Human Nav1.1 And Mechanism Of Channel Dysfunction In Scn1a-Associated Epilepsy, C. Vanoye, Christoph Lossin, T. H. Rhodes, Alfred L. George
Single-Channel Properties Of Human Nav1.1 And Mechanism Of Channel Dysfunction In Scn1a-Associated Epilepsy, C. Vanoye, Christoph Lossin, T. H. Rhodes, Alfred L. George
Christoph Lossin, Ph.D.
Mutations in genes encoding neuronal voltage-gated sodium channel subunits have been linked to inherited forms of epilepsy. The majority of mutations (>100) associated with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) occur in SCN1A encoding the NaV1.1 neuronal sodium channel alpha-subunit. Previous studies demonstrated functional heterogeneity among mutant SCN1A channels, revealing a complex relationship between clinical and biophysical phenotypes. To further understand the mechanisms responsible for mutant SCN1A behavior, we performed a comprehensive analysis of the single-channel properties of heterologously expressed recombinant WT-SCN1A channels. Based on these data, we then determined the …
Non-Inactivating Voltage-Gated Sodium Channels In Severe Myoclonic Epilepsy Of Infancy, T. H. Rhodes, Christoph Lossin, C. Vanoye, Alfred L. George
Non-Inactivating Voltage-Gated Sodium Channels In Severe Myoclonic Epilepsy Of Infancy, T. H. Rhodes, Christoph Lossin, C. Vanoye, Alfred L. George
Christoph Lossin, Ph.D.
Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel alpha(1) subunit (Na(V)1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of five SMEI mutations by using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. Two mutations (F902C and G1674R) rendered SCN1A channels nonfunctional, and a third allele (G1749E) exhibited minimal functional alterations. However, two mutations within or near the S4 segment of the fourth repeat domain (R1648C and F1661S) conferred significant impairments in fast inactivation, including persistent, noninactivating …
Epilepsy-Associated Dysfunction In The Voltage-Gated Neuronal Sodium Channel Scn1a, Christoph Lossin, T. Rhodes, R. Desai, C. Vanoye, S. Caniciu, O. Devinsky, A. George
Epilepsy-Associated Dysfunction In The Voltage-Gated Neuronal Sodium Channel Scn1a, Christoph Lossin, T. Rhodes, R. Desai, C. Vanoye, S. Caniciu, O. Devinsky, A. George
Christoph Lossin, Ph.D.
Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel subunit (Nav1.1) are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density and …
Molecular Basis Of An Inherited Epilepsy, Christoph Lossin, T. H. Rhodes, C. Vanoye, D. Wang, Alfred L. George
Molecular Basis Of An Inherited Epilepsy, Christoph Lossin, T. H. Rhodes, C. Vanoye, D. Wang, Alfred L. George
Christoph Lossin, Ph.D.
Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel alpha1 subunit (NaV1.1), are associated with at least two forms of epilepsy, generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI). We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A. One previously reported GEFS+ mutation (I1656M) and an additional novel allele (R1657C), both affecting residues in a voltage-sensing S4 segment, exhibited a similar depolarizing shift in the voltage dependence of activation. Additionally, R1657C showed a 50% reduction in current density …